RESUMO
Emerging evidence has shown that microRNAs have key roles in regulating various normal physiological processes, whereas their deregulated expression is correlated with various diseases. The miR-146 family includes miR-146a and miR-146b, with a distinct expression spectrum in different hematopoietic cells. Recent work indicated that miR-146a has a close relationship with inflammation and autoimmune diseases. miR-146-deficient mice have developed some abnormal hematopoietic phenotypes, suggesting the potential functions of miR-146 in hematopoietic development. In this study, we found that miR-146b was consistently up-regulated in both K562 and CD34(+) hematopoietic stem/progenitor cells (HSPCs) undergoing either erythroid or megakaryocytic differentiation. Remarkably, erythroid and megakaryocytic maturation of K562 cells was induced by excess miR-146b but inhibited by decreased miR-146b levels. More importantly, an mRNA encoding receptor tyrosine kinase, namely platelet-derived growth factor receptor α (PDGFRA), was identified and validated as a direct target of miR-146b in hematopoietic cells. Gain-of-function and loss-of-function assays showed that PDGFRA functioned as a negative regulator in erythroid and megakaryocytic differentiation. miR-146b could ultimately affect the expression of the GATA-1 gene, which is regulated by HEY1 (Hairy/enhancer-of-split related with YRPW motif protein 1), a transcriptional repressor, via inhibition of the PDGFRA/JNK/JUN/HEY1 pathway. Lentivirus-mediated gene transfer also demonstrated that the overexpression of miR-146b promoted erythropoiesis and megakaryocytopoiesis of HSPCs via its regulation on the PDGFRA gene and effects on GATA-1 expression. Moreover, we confirmed that the binding of GATA-1 to the miR-146b promoter and induction of miR-146b during hematopoietic maturation were dependent on GATA-1. Therefore, miR-146b, PDGFRA, and GATA-1 formed a regulatory circuit to promote erythroid and megakaryocytic differentiation.
Assuntos
Células Eritroides/metabolismo , Eritropoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Megacariócitos/metabolismo , MicroRNAs/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Trombopoese/fisiologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/fisiologia , Células Eritroides/citologia , Fator de Transcrição GATA1/genética , Fator de Transcrição GATA1/metabolismo , Células-Tronco Hematopoéticas/citologia , Humanos , Células K562 , Megacariócitos/citologia , Camundongos , MicroRNAs/genética , Regiões Promotoras Genéticas/fisiologia , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Transdução de Sinais/fisiologia , Regulação para Cima/fisiologiaAssuntos
Infecções por HIV/diagnóstico , Homossexualidade Masculina , Linfoma Difuso de Grandes Células B/diagnóstico , Neoplasias Retais/diagnóstico , Adulto , Fármacos Anti-HIV/uso terapêutico , Antineoplásicos/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/patologia , Masculino , Neoplasias Retais/complicações , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologiaRESUMO
OBJECTIVE: To study the chemical constituents of Choerospondias axillaries. METHODS: All compounds were isolated and purified by normal column chromatograph, paper thin layer chromatograph and sephadex chromatograph, the chemical strucures were mainly elucidated by ESI-MS and NMR spectra. RESULTS: seven compouds were isolated from the Choerospondias axillaries and as following: beta-sitostero (I), hexadecanoic acid (II), correctitude fourty-two alkyl acid (III), daucosterol (IV), quercetin (V), rutinum (VI), lueolin-3'-O-beta-D-glucopyranoside (VII). CONCLUSION: Compounds II, III, V, VII are isolated from this plant for the first time.